The goal of this proposal is to investigate the role of synphilin-1 in the pathogenesis of Parkinson's disease (PD). After Dr. Engelender had done her post-doctoral training in Dr. Ross's laboratory, Dr. Engelender had launched an independent carrier in her original country, Brazil. Dr. Engelender has an independent laboratory at the Department of Anatomy and is waiting for a vacant position to become an Associate Professor. While in Dr. Ross's laboratory, Dr. Engelender had the opportunity to become an expert in the yeast two-hybrid system. This collaboration will be important to find and characterize proteins related to the pathogenesis of PD. PD is a common neurodegenerative disease characterized by tremor, rigidity and bradikynesia. Patients with PD have their symptoms due to death of dopaminergic neurons of the substantia nigra of the brain. It was found that some families with autosomal dominant form of PD have mutations in the a-synuclein gene. A-Synuclein is also an intrinsic component of Lewy bodies of patients with sporadic forms of PD, suggesting that a-synuclein would have an important role in the pathogenesis of PD in general. We found that a-synuclein interacts in vivo with a novel protein called synphilin-1. Synphilin-1 leads to the formation of cytoplasmic inclusions when transfected in mammalian cells together with a-synuclein. In addition, we had just found that synphilin-1 is present in Lewy bodies of PD patients, strengthening our hypothesis that synphilin-1 would also be involved in the pathogenesis of PD. However, similar to a-synuclein, the function of synphilin-1 is still unknown. The main objective of this project is to determine the protein partners of synphilin-1. The identification of protein(s) that interact with synphilin-1, other than a-synuclein, will help to understand its normal function and perhaps the role of synphilin-1 and a-synuclein in PD. In order to determine their relevance to PD, we will study synphilin-1 and synphilin-1 interactor(s) by biochemical and cell biology means. We believe that our approach has the ability to produce unique information regarding the function and role of synphilin-1 and a-synuclein in pathophysiological processes related to PD.